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Structure-Based Design of Nonpeptidic HIV Protease Inhibitors: The Sulfonamide-Substituted Cyclooctylpyranones

1997; American Chemical Society; Volume: 40; Issue: 7 Linguagem: Inglês

10.1021/jm960441m

1520-4804

Harvey I. Skulnick, Paul D. Johnson, Paul A. Aristoff, Jeanette K. Morris, Kristine D. Lovasz, W. Jeffrey Howe, Keith David Watenpaugh, Musiri N. Janakiraman, David J. Anderson, Robert J. Reischer, Theresa Schwartz, Lee S. Banitt, Paul K. Tomich, Janet C. Lynn, Miao-Miao Horng, Kong-Teck Chong, Roger R. Hinshaw, Lester A. Dolak, Eric P. Seest, Francis J. Schwende, Bob D. Rush, Gina M. Howard, Lisa N. Toth, Karen R. Wilkinson, Thomas J. Kakuk, Carol W. Johnson, Serena L. Cole, Renee M. Zaya, Gail L. Zipp, Peggy L. Possert, Robert J. Dalga, Wei-Zhu Zhong, Marta G. Williams, Karen R. Romines,

Click Chemistry and Applications

Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.